Pyridyliodonium salts

ABSTRACT

Pyridyliodonium salts corresponding to the formula   WHEREIN R represents hydrogen, a lower alkyl, an acetamido, a chloro or a bromo group, R&#39;&#39; represents naphthyl, thienyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, phenylphenyl, phenoxyphenyl, di-substituted phenyl in which the substituents are lower alkyl or lower alkoxy, A represents fluoride, chloride, bromide, iodide, trifluoroacetate, trichloroacetate, lower alkanoate, nitrate, acid sulfate, or tetrafluoroborate and n is an integer from 0 to 1. The compounds are useful as antimicrobials for the inhibition and control of the growth of bacterial and fungal organisms.

United States Patent 72] Inventor Zdravko Jezic Midland, Mich. [21 Appl.No. 826,727 [22] Filed May 21, 1969 [45] Patented Nov. 23, 1971 [73]Assignee The Dow Chemical Company Midland, Mich.

I [54] PYRIDYLIODONIUM SALTS 8 Claims, No Drawings [52] US. Cl 260/295S, 260/2948 R, 260/295 AM, 260/297 R, 260/999, 260/294.8 D [51 Int. Cl..C07d 31/44, C07d 31/48 [50] Field of Search 260/297 R, 295 S, 295 AM,294.8 R, 294.8 D

[56] References Cited UNITED STATES PATENTS 3,509,165 4/1970 Ellzey etal. 260/295 Primary ExaminerAlan L. Rotman Attorneys-Griswold & Burdick,John L. Spalding and Theodore Post ABSTRACT: Pyridyliodonium saltscorresponding to the formula wherein R represents hydrogen, a loweralkyl, an acetamido, a

'chloro or a bromo group, R represents naphthyl, thienyl,

phenyl, lower alkylphenyl, lower alkoxyphenyl, phenylphenyl,phenoxyphenyl, di-substituted phenyl in which the substituents are loweralkylor lower alkoxy, A represents fluoride, chloride, bromide, iodide,trifluoroacetate, trichloroacetate, lower alkanoate, nitrate, acidsulfate, or tetrafluoroborate and n is an integer from 0 to l. Thecompounds are useful as antimicrobials for the inhibition and control ofthe growth of bacterial and fungal organisms.

PYRIDYLIODONIUM SALTS SUMMARY OF THE INVENTION The present inventionconcerns the pyridyliodonium salts corresponding to the followingformula In this and succeeding formulas, R represents hydrogen, a loweralkyl, an acetamido, a chloro or a bromo group, R represents napthyl,phenyl, lower alkylphenyl, lower alkoxyphenyl, phenylphenyl,phenoxyphenyl, disubstituted phenyl in which the substituents are loweralkyl or lower alkoxy, A represents fluoride, chloride, bromide, iodide,trifluoroacetete, trichloroacetate, lower alkanoate, nitrate, acidsulfate or tetrafluoroborate and n represents an integer from to l. Theten'ns lower alkyl," lower alkoxy lower alkanoate" refer to groupscontaining from one to four carbon atoms, such as methyl, ethyl, propyl,butyl, methoxy, ethoxy, propoxy, butoxy, acetate, propionate andbutyrate. These compounds are crystalline solid materials which aresomewhat soluble in many common organic solvents and in water. Thecompounds have been found to be of high toxicity to many fungal andbacterial organisms or plants including gram-negative and gram-positivetypes.

Representative pyridyliodonium salts include 3pyridyl-2- thienyliodoniumsalts, 2-butylpyridyl )-(2-thienyl )iodonium salts,5-(Z-acetamidopyridyl)-(2-thienyl(iodonium salts, 5-(2-bromopyridyl)-(2-thienyl)-iodonium salts, naphthyl)iodonium salts,5-(Z-ethylpyridyl)-phenyliodonium salts,5-(2-ethylpyridyl)-(p-ethylphenyl)iodonium salts, 5-(2-acetamido-pyridyl)-(p-methoxyphenyl)iodonium salts, 3-pyridyl-(p-biphenylyl)iodonium salts, 5-(2-chloropyridyl)-(pphenoxyphenyl)iodonium salts,3-pyridyl-(2,4-diethylphenyl)iodonium salts and 5-(2-cholorpyridyl)-(2,4-dimethoxyphenyl) iodonium salts. The term "salt isused in this paragraph to identify the fluoride, chloride, bromide,iodide, nitrate, acid sulfate, trifluoroacetate, trichloroacetate,acetate, propionate, butyrate and tetrafluoroborate compounds.

The pyridyliodonium trifluoroacetates are prepared by reacting togethertrifluoroacetic acid, a 3-(diacetoxyiodo)pyridine and thiophene ornaphthalene or benzene or a substituted benzene compound, i.e., an RHcompound, according to the following equation OCOCH;

+ HR CF3COH OCOGH:

TFA 9 In the equation, and hereinafter, TFA is used to refer totrifluoroacetic acid, while TFA- is used to refer to the anion3-pyridyl-( 2- of 'l' FA. The reaction is advantageously carried out inglacial acetic acid or trifluoroacetic acid or in a mixture of glacialacetic acid and trifluoroacetic acid as reaction medium. In place ofglacial acetic acid, chlorinated solvents such as, for example,methylene chloride, chlorofonn and methyl chloroform'can be used. Thereaction goes forward when the reagents are employed in any amounts. Thereaction consumes the reagents in substantially equimolecular amountsand the employment of amounts which represent about equimolecularproportions is preferred, The reaction proceeds at an acetic acidliberating temperature, e.g., at a temperature of from about minus toabout plus 70 C. and is preferably carried out at a temperature of fromabout minus 20 to plus 40 C. Upon completion of the reaction, thedesired pyridyliodonium trifluoroacetate is separatee by conventionalprocedures.

In a convenient method of carrying out the reaction, the(diacetoxyiodo)pyridine reagent is formed in situ by bringing together a3-iodosopyridine and glacial acetic acid or a mixture of glacial aceticacid and acetic anhydride in which the (diacetoxyiodo )pyridine isformed and dissolved, to the resulting solution is added trifluoroaceticacid while cooling to ca. minus 20 C. and to the so obtained reactionmixture, maintained at ca. minus 20 C., the RH reagent is added withstirring. The reaction is exothermic and goes forward readily with theaddition of the the addition of the RH reagent. The temperature of thereaction mixture is controlled by regulating the rate of the addition ofthe RH reagent and by external cooling. The reaction essentially iscomplete upon completion of the addition of the RH reagent. Allowing theresulting mixture to stand for a period of time at somewhat elevatedtem- 5 pyridyliodonium halide is treated with silver nitrate, silverperatures oftentimes gives some improvement in yield. Upon completion ofthe reaction, the reaction mixture may be distilled under reducedpressure to remove the low-boiling constituents. The residual oil, uponaddition of ether, gives the desired pyridyliodonium trifluoroacetate asa crystalline residue. This residue may be further purified bycrystallization from organic solvents such as, for example, acetone,ethyl acetate, or mixtures thereof with ether.

The pyridyliodonium trichloroacetates are prepared by substitutingtrichloroacetic acid for trifluoroacetic acid in the preceding reaction.Similarly, the acid sulfates are prepared by substituting sulfuric acidfor trifluoroacetic acid in the firstdescribed reaction.

The pyridyliodonium chlorides, bromides, chloride hydrochlorides andbromide hydrobromides are prepared from the correspondingtrifluoroacetates by treatment of the trifluoroacetate with anappropriate gaseous or aqueous hydrogen halide. The amounts of thehydrogen halide reagents to be employed are not critical, some of thedesired halides or hydrohalides being obtained when employing reagent inany proportions. However the reaction consumes the reagent inproportions of l or 2 moles of hydrogen chloride or hydrogen bromide permole of trifluoroacetate, depending upon whether a chloride or chloridehydrochloride, or a bromide or bromide hydrobromide is formed, and theuse of the reagent in amounts which represent such proportions ispreferred. The formation of the halide hydrohalide salts is detected byinfrared analysis (N-H absorption). The reaction takes place readily attemperatures of from 0 to 50 C. with the production of the desiredpyridyliodonium chloride, chloride hydrochloride, bromide'or bromidehydrobromide, respectively, and trifluoroacetic acid of reaction. Duringthe reaction, the halide salts usually precipitate in the reactionmixture as a crystalline solid. Following the reaction, the desired saltproduct is recovered from the reaction mixture. Usually the product iswashed with acetone to remove impurities therefrom and dried at roomtemperature.

The pyridyliodonium acetate, propionate, butyrate, nitrate, andtetrafluoroborate are prepared from the corresponding pyridyliodoniumhalides and conveniently from the corresponding chloride, ln suchoperations, the corresponding tetrafluoroborate or the silver salt of alower alkanoic acid in water or aqueous alcohols as reaction media.There reaction takes place readily with the production of the desiredpyridyliodonium salt product and silver halide. The methods ofcontacting the reagents and conditions of reaction are as described inthe preceding paragraph. Upon completion of the reaction, the desiredsalt product is separated by decantation or filtration.

The pyridyliodonium fluoride salts are prepared in a similar manner byreacting a pyridyliodonium chloride with silver fluoride in an aqueousalcohol as reaction medium. The reaction takes place readily with theproduction of the desired pyridyliodonium fluoride salt product andsilver chloride. The methods of contacting the reagents and conditionsof reaction are as described in the preceding paragraph. Upon completionof the reaction, the desired fluoride salt product is separated from thereaction medium by decantation or filtration.

EXAMPLEl: 3-PYRlDYL-2-TH1ENYLIODONIUM TRIFLUOROACETATE 3lodosopyridine(55.3 g., 0.25 mole) is dissolved in glacial acetic acid (30 ml.), andacetic anhydride (150 ml.) and trifluoroacetic acid (77.5 ml., 1.0 mole)are added thereto with cooling to minus 20 C. Thiophene (42 g., 0.5mole) dissolved in 125 ml. of acetic anhydride is added dropwise withstirring to the so-obtained mixture maintained at minus 20 C. over aperiod of 1 hour. The reaction mixture is stirred at minus 20 for anadditional hour and allowed to warm up to to 50 C. and stirred for anadditional 6.5 hours. As stirring continues at the higher temperature,the reaction mixture gradually turns reddish-brown. Volatile componentsare removed under a pressure of 10-20 mm. Hg at at temperature of 50 to60 C. To the oily residue, ether is added, crude product3-pyridyl-2-thienyliodonium trifluoroacetate crystallizes out, isfiltered ofi, washed with two 50 ml. proportions of ether and dried atroom temperature. The mother liquor is diluted with acetone to anapproximate total volume of 1.5 liters and treated with 10 ml.concentrated HCI to give the product as the 3-pyridyl-2-thienyliodoniumchloride hydrochloride salt. It is filtered ofi', washed with acetoneand dried. The chloride hydrochloride product is recrystallized from 95percent ethanol. The crystalline precipitate is filtered off, washedtwice with 95 percent ethanol and dried in vacuo at room temperature togive an off-white, fine crystalline solid melting at 183 to 184 C. withdecomposition.

The 3-pyridyl-2-thienyliodonium trifluoroacetate crude is recrystallizedfrom ethyl acetate to which decolorizing charcoal is added. Theresulting solution is heated to boiling and Celite filter aid is addedthereto and the solution is filtered. A light tan filtrate is obtained,which, upon standing, yields needlelike crystals which, when filtered,washed with a small amount of cold ethylacetate and dried at roomtemperature in vacuo. gives white needles which melt at 152 to 154 C.with decomposition. The recrystallized trifluoroacetate salt whendissolved in 25 ml. of acetone, filtered and treated with 20 percentaqueous sodium chloride with stirring gives a white crystalline solidprecipitate. The precipitate is filtered off, washed with a small volumeof cold water and a large volume of acetone and is dried at roomtemperature in vacuo. The resulting product, 3-pyridyl-2-thienyliodoniumchloride, melts at 21 1 to 212 C. with decomposition.

Recrystallized 3-pyridyl-2-thienyliodonium trifluoroacetate is dissolvedin 95 percent ethanol, filtered and the clear filtrate treated with afew drops of aqueous 48 percent hydrogen bromide. A white precipitateimmediately forms which is stirred, cooled in an ice bath and filteredto remove crystalline precipitate. The crystals are washed with acetone,dried at room temperature in vacuo and the resulting 3-pyridyl-2-thienyliodonium bromide is found to melt at 194 to 196 C. withdecomposition. The chloride, bromide, chloride hydrochloride and bromidehydrobromide products are identified by elemental and infrared analyses.

- trifluoroacetate.

EXAMPLE 2: 3-PYRlDYL-( p- M ETHOX YPHENYL )lODONlUM CHLORIDEHYDROCHLORIDE A mixture of 10 g. (45 moles) 3-iodosopyridine, 10 g. (93mmoles) anisole and 50 ml. chloroform is stirred at room temperature and10 ml. 15 g., mmoles) TFA is added, dropwise, During addition of the TFAover a 5-minute period, the solid 3-iodosopyridine slowly dissolves, thesolution turns a dark brown color and the temperature rises to 40 C. Thebrown solution is stirred until all the starting iodoso compounddissolves (ca. 15 min.). The solution is then evaporated to a red oiland diluted with 200 ml. ether. The solid which precipitates isfiltered, yielding a tan solid, melting at l49-l 5 0 (dec. The infraredspectrum is consistent with (p-methoxyphenyl )-3-pyridyliodoniumtrifluoroacetate. The trifluoroacetate salt so obtained is dissolved inacetone; treated with decolorizing charcoal overnight; the charcoal isfiltered off; the acetone is boiled off until crystallization begins;and the crystallized product is recovered and dried under vacuum. itmelts at l55.5l56.5 (dec.

Small samples of the purified trifluoroacetate salt dissolved in acetoneare converted to the bromide hydrobromide salt, melting at 17 l-l73(dec.) and to the chloride hydrochloride salt melting at 212 C. (fastdec.) via HBr and HCl. These materials show N-H flilpeaks at 2550 cm.-for the bromide hydrobromide salt and 2380 cmr for the chloridehydrochloride salt. These salts are therefore indicated to be theS-pyridyl-(p-methoxyphenyl)iodonium bromide hydrobromide and the3-pyridyl-(p methoxyphenyl)iodonium chloride hydrochloride,respectively.

EXAMPLE 3: S-PYRIDYL-(p- PHENOXYPHENYL)1ODONIUM BROMIDE To a stirredmixture of 11 g. (0.05 mole) 3-iodosopyridine in 50 ml. chloroform isadded 10 ml. (0.13 mole) of TEA. This dissolves the iodoso compound togive two layers to the mixture, an upper CHC13 layer (colorless) and alower yellow layer of .3-[bk(trifluoroacetoxy)ldo]pyridlne. To thisstirred mixture there is then added 1 l g. (0.065 mole) diphenyl etherfollowed by 5 m1. (0.065 mole) TFA. Within a few minutes, the reactionmixture darkens to a medium brown color.

The reaction mixture is evaporated and diluted with acetone. Addition ofa small excess of aqueous 48% HBr to some of the acetonesolution gives awhite solid melting at 232-235 (dec. To the remainder of the acetonesolution is added a small excess of hydrochloric acid to give a whitesolid, melting at 2 l 2-2 14 (dec. The same results can be achieved bytreating the acetone solution with gaseous HCl or HBr. Theinfraredspectra of both the bromide and chloride salts shows noindication of carbonyl absorption and indicates that alltrifluoroacetate salt is converted to the corresponding halide salt.

In similar procedures, the following compounds of the present inventionare prepared. 3-pyridyl-( lnaphthyl)iodonium trifluoroacetate, m.w.445.18, by reacting S-(diacetoxyiodo)pyridine with naphthalene.

3-pyridyl-(lnaphthyl)iodonium chloride, m.w. 367.62, by reacting thecorresponding trifluoroacetate salt with hydrogen chloride.

5- Z-ethylpyridyl)-(2-thienyl)iodonium fluoride, m.w. 335.13. byreacting the corresponding chloride salt with silver fluoride.

5-( 2-acetamidopyridyl p-methoxyphenyl )iodonium bromide, m.w. 449.10,by reacting the corresponding trifluoroacetate salt with hydrogenbromide.

5-( 2-chloropyridyl p-biphenylyl )iodonium trifluoroacetate, m.w.505.67, by reacting 2-chloro-5- (diacetoxyiodo)pyridine with diphenyl.

5-( 2-bromopyridyl p-phenoxyphenyl )iodonium m.w. 566.13, by reacting2-bromo-5- (diacetoxyiodo)pyridine with diphenyl ether.

5-( 2-bromopyridyl p-phenoxyphenyl)iodonium chloride,

m.w. 488.57, by reacting the corresponding trifluoroacetate-(2-methylpyridyl)-(3,4-xylyl)iodonium chloride, m.w.

359.64, by reacting the corresponding trifluoroacetate salt withhydrogen chloride.

5-(2 -methylpyridyl) (3,4-xylyl)iodonium tetrafluoroborate, m.w. 4l L00,by reacting the corresponding chloride salt with silvertetrafluoroborate.

5-(Z-acetamidopyridyl)-(3,4-diethoxyphenyl)-iodonium trifluoroacetate,m.w. 540.28, by reacting 2-acetamido-5- (diacetoxyiodo)pyridine witho-diethoxybenzene. I

5-( 2-methylpyridyl)-( 3-ethyl-4-ethoxyphenyl)-iodoniumtrifluoroacetate, m.w. 481.25, by reacting 2-(diacetoxyiodo)-S-methylpyridine with o-ethoxyethylbenzene.

5-(2methylpyridyl)-(3-ethyl-4-ethoxyphenyl)-iodonium chloride, m.w.403.69, by reacting the corresponding trifluoroacetate salt withhydrogen chloride.

5-(2-methylpyridyl)-(3-ethyl-4-ethoxyphenyl)-iodonium nitrate, m.w.430.24, by reacting the corresponding chloride salt with silver nitrate.

The compounds of the present invention are .useful as microbicides. Theyhave high toxicity toward many bacterial organisms or plants includinggram-negative and gram-positive types such as Staphylococcus aureus,Salmonella typhosa, Bacillus subtilis, Escherichia coli, Pseudomanasaeruginara, Candida pelliculosa, Aspergillus terreus and Aerobacteraerogenes'. This is not to suggest that all of the compounds are equallyeffective against the same organisms or at similar concentrations. Thecompounds may be applied to many bacterial plants and their habitats inbactericidal amounts to obtain excellent controls of the microbialorganisms which attack the seeds, roots or above-ground portions ofterrestrial plants. For such uses, the unmodified compounds can beemployed. The compounds can also be dispersed on an inert finely dividedsolid and employed as dusts. Such mixture can also be dispersed in waterwith or without the aid of a surface active agent and employed assprays. In other procedures, the products can be employed as activeconstituents in solvent solutions, aqueous dispersions or oil-in-waterand water-in-oil emulsions. Good results are obtained with methodsemploying and compositions containing microbicidal or antimicrobialamounts of the novel compounds. Preferred compositions contain from 0.1to 50 percent by weight of compound. The compounds may be included inadhesives, cooling waters, inks, plasticizers, latices, resinouspolymers, fuels, greases, soaps, detergents, cutting oils and oil orlatex paints to prevent mold and mildew and the degradation of suchproducts resulting from microbial attack. Also, it has been discoveredthat the compounds advantageously may be distributed in textiles,fabrics, and paper or other cellulosic products, or may be employed inthe impregnations of wood, lumber, wallboard and plaster to protect suchproducts form the attack of the bacterial organisms of rot, mold, mildewand decay.

The exact concentration of the toxicants to be employed in the treatingcompositions is not critical and may vary considerably provided therequired dosage of the effective agent is supplied in the ink, adhesive,soap, detergent, fuel, grease, cutting oil, plasticizer, resin,polymeric material, paint, textile, fabric, paper, wood or growth mediumor upon the terrestrial plant foliage or fruit. The concentration oftoxicant in liquid compositions generally is from about 0.0l to 50percent by weight. Concentrations up to 95 percent by weight areoftentimes conveniently employed ln dusts, the concentrations of thetoxicant can be from about 0.1 to 95 percent by weight. In compositionsto be employed as concentrates, the toxicants can be present in aconcentration of from 5 to 98 percent by weight.

In representative operations, each of (3-pyridyl)-(2-thienyl)iodoniumchloride hydrochloride andthe corresponding trit'luoroacetate 3-pyridylp-methoxyphenyl )iodonium chloride hydrochloride; and(3-pyridyl)-(p-phenyoxyphenyl)iodonium bromide gives 100 percent kill ofStaphylococcus aureus, Bacillus subtilis, Mycobaclerium phlei and 6 aTrichophyion menragrophytcs when; employed in aqueous acetonecompositions at a concentration of 500 parts per million by weight.

In further operations, each of 3-pyridyl)- 2-thienyl)iodonium chloridehydrochloride and mo, corresponding trifluoroacetate gives percent killof Pseudomonas aeruginosa, Escherichia 'coli, Salmonella typhaea andPseudomonas Sp. Strain 10 ,when employed in aqueous acetone compositionsat a concentration of 100 parts per million by weight.

The starting (diacetoxyiodo)pyridine compounds are prepared by reactinga corresponding iodosopyridine with glacial acetic acid according to thefollowing equation:

I0 (000011.), Bio

+ ZCHsCOOH r N I N a v Rh The reaction is advantageously carried outinthe presence of reactants to be employed are not critical, some of theproduct being fonned when employing any proportions. The reactionconsumes the reactants in the ratio of 1 mole of the iodosopyridinecompound to 2 moles of acetic acid, and the employment of suchproportions is advantageous. However superior yields are obtained whenusing up to about l0 times the stoichiometric amount of acetic acid. Thereaction proceeds at a temperature at which water of reaction isliberated, suitably at a temperature between 0 and 50C.

In carrying out the reaction, the iodosopyridine and the acetic acidreactant are contacted in any convenient fashion and maintained for apredetermined period of time in the reaction temperature range tocomplete the reaction. In a representative procedure, the iodosopyridinereactant is added to well-stirred glacial acetic acid. During theaddition of the iodosopyridine reactant to the acid and for a periodthereafter, the temperature of the reaction mixture is maintained withinthe reaction temperature range.

Upon completion of the reaction, the desired product is recovered byconventional procedures. To illustrate, excess glacial acetic acid isevaporated under vacuum at a temperature less than 50 C. or may simplybe blown off with air at room temperature.

What is claimed is:

l. The compound corresponding to the formula I a (R is wherein Rrepresents hydrogen, a lower alkyl, an acetamido, a chloro, or a bromogroup, R represents naphthyl, phenyl, lower alkylphenyl, loweralkoxyphenyl, phenylphenyl phenox yphenyl, disubstituted phenyl in whichthe substituents are lower alkyl or lower alkoxy, A represents fluoride,chloride, bromide, iodide, trifluoroacetate, trichloroacetate, loweralkanoate, nitrate, acid sulfate or tetrafluorobora'te and n representsan integer from 0 to l.

2. The compound of claim 1 wherein R is 2-thienyl, A is chloride, andhis I. l

3. The compound of claim 1 wherein R is 2-thienyl, A is yl, A ischloride, and n is 0.

i t i i

2. The compound of claim 1 wherein R'' is 2-thienyl, A is chloride, and n is
 1. 3. The compound of claim 1 wherein R'' is 2-thienyl, A is trifluoroacetate and n is
 0. 4. The compound of claim 1 wherein R'' is 2-thienyl, A is chloride, and n is
 0. 5. The compound of claim 1 wherein R'' is p-methoxyphenyl, A is chloride, and n is
 1. 6. The compound of claim 1 wherein R'' is p-methoxyphenyl, A is trifluoroacetate, and n is
 0. 7. The compound of claim 1 wherein R'' is p-phenoxyphenyl, A is bromide, and n is
 0. 8. The compound of claim 1 wherein R'' is p-phenoxyphenyl, A is chloride, and n is
 0. 